A computational biologist's personal views on new technologies & publications on genomics & proteomics and their impact on drug discovery

Wednesday, May 18, 2016

Exploring Critiques of Siddhartha Mukerjee's The Gene, An Intimate History

My finely tuned skills in the art of procrastination KOed my plans to see Siddhartha Mukerjee's talk tonight at a local bookstore (apparently with Henry Louis Gates) to promote Mukerjee's new book The Gene: An Intimate History -- the event sold out. Perhaps I could have found a scalper, but I decided I'd just head home. Mukerjee's first book, the cancer history The Emperor of All Maladies, was very well received (even spawning a PBS series), and I was impressed that Mukerjee took the time to contact me after I wrote a review in this space. The new book has been taking quite a bit of criticism, and even more so his New Yorker piece that preceded it (and I assume is derived from a portion of the book).

I won't comment in depth on the New Yorker epigenetics hullabaloo, but Mukerjee really invited a firestorm by not only wading into epigenetics, but also touching on the still up-in-the-air area of epigenetics and schizophrenia. I haven't read the book yet, and perhaps he covers these, but I might have suggested two very interesting and better nailed down epigenetics in medicine topics which I covered in 2011. One is how mutations in an important histone mark mediator, EZH2, can lead to cancer. The other is how a mutation in a central metabolic enzyme, isocitrate dehydrogenase (IDH), can alter the methylation marks on DNA and again lead to cancer. Since I wrote that piece, the company Agios has had very promising clinical results with a drug that blocks mutant IDH and shifts the pattern of methylation closer to wild-type, resulting in the cells returning to their normal pattern of differentiation and (more importantly) being mortal. (full disclosure: I consulted for Agios briefly between jobs, but I've (sadly) never held any equity in them).

What I would like to dive into is some of the exquisite scrutiny that Mukerjee's statements of facts have been receiving. Mukerjee aspired to write a history, and I agree it is important to get things right. In particular, where small errors of fact obscure or distort larger patterns, corrections are important and often enlightening. For example, Matthew Cobb points out that rather than Gregor Mendel being a lone researcher working an idiosyncratic program (which is certainly how everything I've ever read has suggested things, and Mukerjee is apparently no different), Mendel's abbot had a long-standing interest in heredity and breeding and efforts predated Mendel's work by two decades. This abbot (who Mendel would replace), Cyril Napp, is sadly very obscure; for example, at this moment, he lacks his own Wikipedia page and is barely mentioned in Mendel's.

On the other hand, Cobb strays a bit when he faults Mukerjee for "A brief footnote describes Vernon Ingram and Francis Crick's ground-breaking 1950s demonstration that the difference between normal and sickle-cell haemoglobin is caused by a single-base difference in the relevant gene" I agree, this is a pretty awful relegation, but on the other hand Ingram didn't really nail things down to a single nucleotide; the technology to do that was far in the future, as was even the elucidation of the genetic code. Ingram points out in a published memoir article that what his work did do was kill some of Francis Crick's ideas about overlapping codes (which Crick called "comma free", a term that has never appealed to me), since they could not accommodate easily a mutation causing only a single amino acid to change.

Cobb's review was relatively gentle; a piece in The Atlantic by Nathaniel Comfort is not, decrying the book as "whig history". To my tastes, Comfort's criticisms veer into pedantry without being illustrative. Comfort goes after Mukerjee's assertion that Darwin missed filling a key gap in his theory by not reading Mendel, who had famously sent a copy of his book to Darwin. Comfort goes after Mukerjee for imposing a very modern interpretation of Mendel's work onto Mendel; he wasn't studying digital, physical genes but more abstract "elements" and hybridizations. This is a line that is also pursued in a chapter of the book Newton's Apple and Other Myths of Science. Fair enough -- but the key point is now obscured that indeed Mendel had illustrated a non-blending form of trait inheritance, and a blending mode was much more problematic for a theory of evolution, which Comfort seems not to grasp: "Moreover, Darwin understood his own theory perfectly: It assumes that heritable variation occurs, but it does not depend on knowing where that variation comes from". So, in my humble opinion, Comfort's half-baked correction obscures as much as it enlightens.

As an aside, when I was at Harvard Matt Meselson had asserted (at least, in my memory he did) stated that Mendel had sent a copy of his booklet to the Boston Public Library. I had asked Matt if he had ever tried to find out how had checked out the book, and he confessed he had never thought to do that. On New Year's Eve, I found myself in the unusual situation of being in Boston on holiday on a weekday, so TNG and I went to the main BPL branch so I could view a rare and expensive coffee table book on matte painting, which as rumored had many mentions of my uncle's art (unsurprising, since one of his daughters wrote a glowing review on Amazon). It is a spectacular look at the technology. Anyway, since I was there, I thought I'd venture into the rare book room to look for Brother Mendel's work, but alas, there is no original edition of Mendel in the BPL's catalog.

Comfort's other attack concerns attitudes towards DNA, as espoused in the remark that DNA is "a stupid molecule". Mukerjee apparently assigns this quote to the wrong individual (Phoebus Levene) and uses it as an illustration of the surprise to many that DNA was the carrier of genetic information; the quip is apparently from Max Delbrück and was meant sarcastically. Comfort really goes out a ledge on the topic of DNA

This approach lets us see that DNA was not the “underdog of all molecules.” Its structure was considered anything but “comically plain.” Nobel Prizes were awarded three times for elucidating aspects of it: in 1910 (Albrecht Kossel), 1957 (Alexander Todd), and 1962 (Watson, Crick, and Wilkins).

Okay, let's parse this. I was sadly ignorant of the first two scientists mentioned, so time for digging. Kossel won his prize for identifying the 5 bases found in nucleic acids, but no hint yet of DNA or RNA as an information carrier. Todd won his prize largely for studying the role of nucleotides as coenzymes in proteins, not for information transfer. And in any case, by 1957 the pivotal role of DNA as the carrier of heredity was well-established.

What Comfort is completely blowing past here is that there was widespread resistance to the idea of DNA as an information carrier, with protein favored by many. Even proteins weren't universally understood in the 1940s to be orderly and ordered; Fred Sanger was rejected on a grant to try to sequence proteins, because reviewers did not believe a defined sequence was present. It is also worth remembering that Claude Shannon's work on information theory was new and probably not read by any biologists. Conversely, encoding complex patterns in 2-state (binary) or 3-state (Morse, if you count the necessary pauses between letters) codes had been well established, with uses ranging from player pianos to Jacquard looms to telegraphy. Cobb, in another piece, describes how Avery's evidence for DNA as the transforming principle (i.e. carrier of hereditary information) was fiercely resisted by Avery's colleague Alfred Mirsky, and that the model for nucleic acids generated by Levene was far too simple to carry information -- Levene posited that nucleotides were organized as tetranucleotides, with all four nucleotides present in each tetranucleotide.

Getting facts right is hard; correcting them is perhaps harder. If I have in turn failed in debunking the debunkers, please do chastise me in the comments (with citations please!). Mukerjee's book joins Cobb's own history of genetics on my to read list, and perhaps after I do so I'll find more issues to bat about.

1 comment:

Anonymous
said...

Keith - very informative post. I've only flipped through The Gene but was disappointed with Mukerjee's version of the history of the Human Genome Project, which is the NIH's version. He mentions the DOE in passing but not the three key meetings in 1984 and 1985, or events like the first DOE HGP grant in 1987, but jumps instead to 1989, with James Watson and Eric Lander as the apparent pioneers. Along with his much-publicized complete omission of transcription factors in favor or epigenetic factors in the recent New Yorker article, this tells me that I'd be reading a biased or incomplete or superficial book. Not terribly motivating.

Also, one correction about IDH mutations: Agios's inhibitors can make cells harboring the mutations re-differentiate, assuming there are no other mutations preventing this, but they do not necessarily make the cells mortal again, since the mutations can happen in stem cells.

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About Me

Dr. Robison spent 10 years at Millennium Pharmaceuticals working with various genomics & proteomics technologies & working on multiple teams attempting to apply these throughout the drug discovery process. He spent 2 years at Codon Devices working on a variety of protein & metabolic engineering projects as well as monitoring a high-throughput gene synthesis facility. After a brief bit of consulting, he rejoined the cancer drug discovery field at Infinity Pharmaceuticals in May 2009. In September 2011 he joined Warp Drive Bio, a startup applying genomics to natural product drug discovery. Other recurring characters in this blog are his loyal Shih Tzu Amanda and his teenaged son alias TNG (The Next Generation).
Dr. Robison can be reached via his Gmail account, keith.e.robison@gmail.com
You can also follow him on Twitter as @OmicsOmicsBlog.